Anti-Cancer Metastasis Treatment

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We had earlier shown that cancer dissemination is controlled by aberrant expression or splicing of metastasis genes. We recently found that metastatic gene expression patterns are generally characterized by a core program of gene expression that induces the oxidative metabolism, activates vascularization/tissue remodeling, silences extracellular matrix interactions, and alters ion homeostasis. This program distinguishes metastases from their originating primary tumors as well as from their target host tissues. (Hartung et al. A core program of gene expression characterizes cancer metastases. Oncotarget 2017;8:102161. Hartung et al. Site-specific gene expression signatures of cancer metastases. Clin Exp Metastasis, DOI 10.1007/s10585-019-09995-w 2019). We are exploring ways to target the core signature with suitable drug combinations.

Nuclear Osteopontin

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The cytokine Osteopontin is an important progression mediator in over 30 cancers. This lab has contributed some of the most significant advances to understanding the underlying mechanisms. We have reported the importance and uniqueness of Osteopontin splicing in cancer. Several Osteopontin variants are expressed in invasive, but not in non-invasive, human tumor cells. These splice variants may be indicators for progression or recurrence risk and for treatment responses (He et al.  An osteopontin splice variant induces anchorage independence in human breast cancer. Oncogene 2006;25:2192. Zduniak et al. Osteopontin variants in breast cancer treatment responses. BMC Cancer 2016;16:441.Walaszek et al. Breast cancer risk in premalignant lesions: Osteopontin splice variants indicate prognosis. Brit J Cancer 2018;119:1259). In some cancer cells, spliced osteopontin is present in the nucleus. We are studying the role of nuclear osteopontin in cancer progression.

Mitochondrial Effects by Osteopontin

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Cancer metabolism has experienced a renaissance of research interest since 2006. We were among the first groups to report that cancer cell metabolism during metastasis is dramatically different from the much-studied Warburg effect. Enhanced energy production is a prerequisite in this process. Osteopontin-c supports anchorage-independence through inducing oxidoreductase genes that are associated with the mitochondrial energy metabolism and with the hexose monophosphate shunt. The Osteopontin-a-induced glucose uptake fuels this process. (Shi et al. Osteopontin-a alters glucose homeostasis in anchorage independent breast cancer cells. Cancer Lett 2014; 344:47. Shi et al. Energy metabolism during anchorage independence. Induction by osteopontin-c. PlosOne 2014;9:e105675. Weber. Metabolism in cancer metastasis. Int J Cancer 2016;138:2061). The impact of Osteopontin on mitochondrial function is incompletely elucidated. We are working on deepening our understanding of it.